Neuropilin 1 (NRP1) was originally identified as a neuronal semaphorin 3A receptor that mediates axonal extension during embryonic development. It was later discovered to be present in endothelial cells, mediating angiogenesis during development and in lung cells, controlling lung branching during development (Roche J, et al., Adv Exp Med Biol 2002, 515:103-114). NRP1 is a type I transmembrane glycoprotein and a coreceptor for two extracellular ligands, semaphorins/collapsins, and vascular endothelial growth factor (VEGF; Ferrara N, et al., Nat Med 2003, 9:669-976). VEGF mediates tumor angiogenesis and directly enhances tumor growth via VEGF/VEGF receptor (VEGFR) autocrine loops in tumors (Dias S, et al., Proc Natl Acad Sci USA 2001, 98:10857-10862). NRP1 forms complexes with Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2) to enhance the binding of VEGF165 to VEGFRs and promotes VEGF165-mediated tumor angiogenesis, cell migration, and tumorigenicity (Murga M, et al., Blood 2005, 105:1992-1999).
NRP1 has been observed in cancer cells, including PC3 prostate cancer cells and metastatic MDA-MB-231 breast cancer cells as well as several other types of tumor cells (Lee M., Mol Cancer Ther 2006, 5:1099-1107). Overexpression of NRP1 enhances tumor angiogenesis and tumor growth in vivo (Klagsbrun M, et al., Adv Exp Med Biol 2002, 515: 33-48). NRP1 expression is present in various human cancers (Ellis LM. Mol Cancer Ther 2006, 5:1099-1107) and is associated with increased tumor aggressiveness and neovascularization; however, its modes of action are not fully understood.
Lung cancer is the most common cause of cancer deaths, accounting for 17% of deaths from cancer (Shibuya K, et al., BMC Cancer 2002, 2:37). Non-small cell lung carcinoma (NSCLC) is the predominant type of lung cancer (Hoffman P C, et al., Lancet 2000, 355:479-485). Metastasis is the major cause of treatment failure and cancer deaths (Kwong Y L, et al., Chest 1997, 112: 1332-1337). The identification of metastasis enhancers and their signaling pathways may improve our understanding of the metastatic process and provide future targeted therapy for NSCLC patients.